Environmental influence on reproductive tract function

National Institute Of Environmental Health Sciences

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Abstract

Different environmental chemicals can affect the reproductive capability of a variety of organisms, depending on the timing and dose of exposure, and are thought to impact human reproduction as well. One example is the phytoestrogen, genistein, which when given to neonatal female mice has long-term effects on their ability to reproduce. The underlying causes of their infertility, however, are not known. A second example is diethylstilbestrol, which causes reproductive tract malformations when given prenatally (before birth) and reproductive tract dysfunction and cancer when given neonatally (around the time of birth). We are using both neonatal genistein and DES treatments to determine how estrogenic compounds affect female reproductive tract development and function. These studies are relevant to human fertility because genistein levels similar to those reached in our mouse model are measured in babies on soy-based infant formula, and many other estrogenic compounds are found in the environment and could affect reproductive tract development and function. Female mice treated neonatally with DES are infertile at reproductive age and develop uterine cancer as older adults. We performed a series of experiments to determine how the neonatal exposure changes gene expression profiles in the adult uterus that may explain these phenotypes. We published work showing that neonatal DES exposure causes genome-wide changes in epigenetic marks at enhancer regions of altered genes at the completion of treatment on postnatal day 5. We are now performing studies to examine on a genome-wide basis whether there are alterations in additional epigenetic marks such as DNA methylation in the uterus after neonatal DES exposure. We are also examining whether these marks persist in adults. We have also published work describing in detail the molecular phenotype of the abnormal endometrial cells that develop in the uterus following neonatal DES exposure and are found in the cancer lesions in adults. We are using knockout mouse models to test whether specific molecules are drivers of cancer development; this work is ongoing.